Locked-in
syndrome (LIS) is a rare and difficult condition to recognize by clinicians,
especially the non-neurologists.[1-33]
This syndrome poses serious challenges to the
clinicians both in terms of the diagnosis and management, for it may be
confused with stroke and other causes of unconsciousness. To the non-specialist
doctor the patient appears unconscious; such a belief may lead the clinician to
a wrong diagnosis and inappropriate management of the patient, especially if
the doctor fails to examine vertical ocular movements. Another danger is that
the attending doctors and nurses may discuss the “unconscious” patient’s
condition at the bedside, to the hearing of the patient, which may enormously
stress the patient and cause deterioration of the condition.

The
syndrome is characterized by quadriplegia and anarthria in a patient with
preserved consciousness: [2-13]. The patient is motionless
and mute, but retains the ability to open and blink the eyes and move them
vertically. The diagnosis in most cases, is made after a family member or
hospital nursing staff calls the attention of the doctor to the fact that the
patient, who appears comatose is awake and aware of his immediate surroundings
or if MRI shows a ventral pontine lesion, coupled with a normal EEG in an
otherwise unresponsive patient. It is known that cerebral infarction or
haemorrhage, brainstem trauma, demyelinating disease, tumours and encephalitis
[5-7;14] can cause LIS, especially
when these lesions affect the ventral portion of the lower pons and medulla,
although demyelinating diseases are rare in the African continent. The prevalence
of MS is less than 1 per 100,000 in the equatorial area (e.g. Nigeria) and
blacks are at lower risk than whites in all latitudes. There are no reports in
the literature of LIS in an African with multiple sclerosis. We saw such a
patient in our practice at the University of Calabar Teaching Hospital,
Calabar, Nigeria, whom we followed-up until his death. We hereby report this
interesting case, to enhance easy recognition of the syndrome by all
clinicians, especially those practicing in developing countries.

Case
Report

1.The
First Episode

A
41 – year old Nigerian male university lecturer was previously well until the
day his wife first noticed some degree of unsteadiness in his gait, while
walking. This did not bother him until about 2 months later when he complained
of weakness in all four limbs. Days later, while waiting to address a
conference, the weakness suddenly became so profound that someone else had to
take–over the reading of his prepared conference paper. At the end of the
conference, he was driven home by his wife, as he was too weak to do so
himself. Few hours later, when he became completely paralyzed in all 4 limbs
and could no longer talk, he was taken to the University of Calabar Teaching
Hospital, Calabar, Nigeria, where he was admitted the same day. His past
medical history contained nothing that could point to the cause of his illness:
no history of hypertension, diabetes mellitus, stroke, head injury, psychiatric
illness or other chronic illnesses or recent neuro-infections. He was married
with four children.

On
physical examination: patient was lying motionless, with opened eyes, which
blinked occasionally. He could not speak, but tried to communicate with the
eyes, which could move in the vertical plane only. Patient reacted to what
people said and other happenings in his immediate environment, by moving the
eyes or blinking them; meaning that the motionless and mute patient was indeed
conscious. The chest: no respiratory distress, clinically clear; BP: 130/80 mm
Hg; abdomen: no abnormalities. Neurological status: decerebrate posturing;
signs of corticospinal tract dysfunction– quadriplegia, spasticity and
exaggerated deep tendon reflexes in all 4 limbs; and bilateral cranial nerves
palsies (3rd, 6th and 7th). Based on the above clinical findings, a
diagnosis of locked – in syndrome (cause?) was made. On admission: full blood
count, red cell sedimentation rate, blood sugar, urea, electrolytes, creatinine
and liver function were all normal. VDRL was negative. On the 2nd day, before
other planned investigations (e.g CSF and x–ray examinations etc) could be
conducted, patient was taken out of hospital by his family members, against
medical advice. At home, because of the “mutism”, suspected to be due to
depressive psychoses, a patient’s relation, a pharmacist, on her own
initiative, introduced an anti –depressant drug to the therapy, with no
positive effect. Next they took him to a pastor of a church, for divine
healing.

The
patient was in the motionless– mute state for 5 months. From the 6th- 8th
months, according to the wife, without further medical care, apart from
occasional physiotherapy, functions gradually returned: initially
movements in the upper limbs resumed, followed by ability to sit up and
the use of his lower limbs. Later the speech gradually improved. About a year
after the onset of illness, patient, not discouraged by residual neurologic
deficits (namely, spastic gait and speech disorder) , resumed duty at his
workplace.

A repeat
neurological evaluation 7 months after he resumed duty revealed intact
cognitive functions. However, he complained of unsteadiness in walking, hearing
difficulty, with buzzing sound in both ears like the sound of an approaching
aeroplane. He could not recall most of the events of the past months of his
illness. On examination: mild quadriparesis with dysarthria; audiometric test:
bilateral sensorineural deafness (worst on the left); fundoscopy: bitemporal
pallor; computerized tomography (CT) of the brain showed slightly dilated
lateral ventricles, without suggesting its definitive cause in this particular
case: normal EEG.

The
buzzing sounds in the ears cleared completely by the 21st month of illness; but
hearing difficulty and unsteady gait persisted. Patient had to wear hearing
aids.

2.Second
Episode

In
the 32nd month of illness, patient suffered yet another attack: unsteady gait,
severe weakness of the four limbs and profound speech disturbance. Generally,
the presentation reminded the family members of the 1st attack. Consequently
the family once again called in the Pastor of his Church, for spiritual
healing. Three weeks later, when patient’s condition further deteriorated, he
was brought to the hospital. Neurological evaluation revealed: dementia; a
motionless patient, quadriplegic, unable to talk, sit-up or walk; painful
flexor/extensor spasms; cranial nerves palsies (3rd, 6th and 7th). The
relapsing nature of the disease, with symptoms/signs indicative of
multi–focal central nervous system involvement, together with the
failure of CT scan to identify lesion suggestive of pontine haemorrhage or
infarction, tumour or brainstem trauma, raised the suspicion, that ventral
pontine demyelination (multiple sclerosis) may be the most likely cause of our
patient’s Locked – in Syndrome, and that the attacks (episodes 1 and II) were
exacerbation of the multiple sclerosis. Prompted by this realization, the
management of the case was reviewed, and included (i) corticosteroid
(prednisolone) therapy and (ii) Baclofen, for the treatment of spasticity and
the painful flexor/extensor spasms. In the next two months, patient’s condition
gradually improved, the spasticity became less incapacitating with time. The
speech too improved during the 2 – month stay in hospital. But in one occasion,
patient’s condition deteriorated drastically: for the first time, during the
course of illness, he lost consciousness, for about 6 hours. Investigations
revealed; (i) normal chest x-ray (excluded pneumonia) and (ii) asexual P.
falciparum parasitaemia (confirmed severe malaria as the trigger for the
deterioration of the patient’s condition). Patient responded dramatically to a
course of anti-malaria drug therapy (with fansidar): regained full
consciousness within 12 hours. Satisfied with the level of improvement of his
mental state, motor function and speech, patient was discharged home by his
doctors, at the end of a 2-month stay in the hospital. By the 4th month, the
patient had recovered most functions and was well again.

3.Death
of Patient

8
months after discharge from hospital, patient’s condition once again
deteriorated: at first he was febrile; and later became quadriplegic and
comatous. He was rushed to a nearby private hospital, where chest x-ray
examination revealed pneumonia. Before appropriate antibiotic therapy could be
initiated the patient died. The family did not allow autopsy.

Discussion

Case
Definition

Emile
Zola, [15] a non-medical writer, was the first in 1868, to
describe a woman with this syndrome in a book “Therese Raquin”. However, it was
more than hundred years later that Plum and Posner [16] introduced the term
“Locked-in Syndrome”.

LIS
was first re-defined in 1966 as quadriplegia, lower cranial nerve paralysis and
mutism, with preservation of consciousness, vertical gaze and upper eyelid
movements [16]. So that mutism would not be mistaken for
unwillingness to speak,[17] in 1986, LIS was again
re-defined as a syndrome characterized by quadriplegia and anarthria, with
preservation of consciousness.[18]

The
locked-in patient is usually conscious, while lying mute and motionless. He
retains blinking and voluntary vertical eye movements, which facilitate
non-verbal communication [1-14,19].
That means, the patient is aware of his surroundings, but is physically
locked-in.[12,13] Some cases may
exhibit decerebrate posturing.[6]

One
could logically refer to this state as akinetic mutism since the patient is
akinetic (motionless) and mute, but this condition originally coined by Cairns
[12], is somewhat different in that the lesion of akinetic
mutism lies in the cerebral hemispheres hence the patient is unaware of his
surrounding but shows sleepwake-cycle and may be able to withdraw from a
painful stimulus.

Pathologic
Basis of LIS

The
pathophysiology of LIS involves a lesion affecting the ventral portion of the
lower pons or medulla with the sparing of the upper pontine tegmentum.[6;14] The diencephalons and the ascending
reticular formation responsible for consciousness lie above the mid pons hence
consciousness is preserved in these patients. Thrombosis of the upper segment
of the basilar artery resulting in infarction, haemorrghage, trauma (brainstem
contusion or vertebro-basilar axis dissection), viral brainstem encephalitis,
central pontine myelinolysis, demyelinating disease (acute or chronic relapsing
multiple sclerosis), and primary and secondary tumours, all affecting the
ventral pons or medulla, are the usual causes of locked-in syndrome [2,6-9,13,14]. There are reports also, that severe Guillian Barre
Syndrome [20] and snakebite [21;22] may cause LIS.

A
lesion at the mid pontine level, while sparing the somatosensory pathways, may
interrupt [2-5,17,18,23,24] the corticobulbar and
corticospinal tracts to the lower cranial nerves and the limbs, resulting in the
paralysis of all four limbs, face and pharynx and larynx. The bilateral
facio-glosso-pharyngo-laryngeal paralysis [25] causes
anarthria, dysphagia and limits the use of the muscles of facial expression in
communication [2]. These factors may explain why the
locked-in patient is motionless, quadriplegic and mute, but conscious, as it
was the case with our patient.

Vertical
eye movements are controlled from a centre in the superior collicular region of
the midbrain and are thus preserved together with the pupillary light reflex [13]. A mid pontine lesion is likely to affect the abducens
nucleus and cause the loss of lateral gaze, which is a feature of the disease
as manifested in this case. The preserved partial eye control can therefore be
utilized to affirm awareness in the patient by ordering him to open and close
the eyes.

The
ataxia associated with this condition and experienced by our patient most
probably arises from the involvement of the pontine nuclei and the fibers which
connect the pons with the cerebellar hemispheres. The lower part of the pons
contains a number of neurons and fibres connecting the pontocerebellar and
corticopontine tracts. All voluntary movements originate from the cerebral
cortex with simultaneous transmission to the cerebellar cortex via the nuclei
pontis. The activities of the cerebellar cortex initiated in this way are
immediately relayed back to the cerebral cortex via the superior cerebellar
peduncles. Any lesion affecting this circuit is bound to present with ataxia.

This
patient also experienced buzzing sound in both ears, which took more than two
years to clear, and sustained a permanent hearing defect in both ears. These
auditory disturbances may suggest pontine auditory hallucinosis (i.e. complex
auditory illusions with some qualities of hallucination, which may accompany
pontine lesion). Auditory hallucinosis consists of alternating musical tones,
like an organ or a jumble of sound (like a symphony Orchestra tuning up) or
siren- like or buzzing sound, like a swarm of bees.

These
auditory sense disturbances are more complex than neurosensory tinnitus but
less formed than temporal lobe hallucinations. They are usually associated with
impairment of hearing in one or both ears and other neurologic signs related to
the pontine lesion (as in our patient). Brainstem evoked potentials may reveal
intact cochlear, auditory nerve and cochlear nuclear responses, although our
patient showed a bilateral sensorineural deafness.

The
mild dilatation of the lateral ventricles in this case may indicate some degree
of obstruction of the ventricular system; but we cannot use this to explain LIS
in our patient as the computerized tomography did not suggest the actual cause
of this dilatation and there was no history to suggest tumour or support a
vascular aetiology (cerebral haemorrhage or infarction) of LIS in our patient.

Diagnosis

Locked
–In Syndrome

The
diagnosis of LIS [1,2,5,33], in most cases, is made when family members or hospital
nursing staff call the attention of doctors to the fact, that the patient, who
appears comatous, is awake and aware of his immediate surroundings or if MRI
shows a ventral pontine lesion, coupled with a normal EEG, in an otherwise
unresponsive patient. In such cases, it is mandatory for the doctor to assess
voluntary eye opening and blinking abilities and vertical eye movements [6]. These brainstem- mediated movements are preserved in LIS.
CT scanning, MRI and auditory evoked response are some of the sensitive tests
that can be used to investigate the brainstem of LIS patient. Unfortunately, we
did not have these facilities in our practice. A conventional EEG with
stimulation can distinguish between LIS (normal EEG, as it was with our
patient) and coma (abnormal EEG).

Multiple
Sclerosis (MS)

Initially
the MS patient presents with an unsteady gait, spastic paraparesis, retrobulbar
neuritis, diplopia and sphincter dysfunction [6,14].All or most symptoms may disappear after a few
days/weeks/months. Our patient presented with most of these initial symptoms.
Infections, trauma or pregnancy can trigger exacerbation of this disease.
Diagnosis of MS is based on the total clinical picture that indicates the
involvement of different parts of the central nervous system (CNS) at different
times. [6,14]

The
multiple CNS lesions in MS are detectable by electrocerebral responses evoked
by: (i) monocular visual stimulation with checkerboard patterns (visual evoked
potentials, VEP); monaural stimulation with repetitive clicks (brainstem
auditory evoked potentials, BAEP); and electrical stimulation of a peripheral
nerve (somatosensory evoked potentials, SSEP) [6;19]. MRI too has become nearly indispensable in confirming
the diagnosis of MS [6]. These facilities were not
available for the management of our patient.

The
Cerebro-Spinal Fluid (CSF) is commonly abnormal [6]: mild
lymphocytosis or slightly increased protein concentration, especially soon
after an acute relapse. Spinal tap was not done, because the relations did not
create the opportunity for us to do this relatively simple procedure. CSF
protein electrophoresis could have shown the presence of discrete bands in the
1gG region (oligoclonal bands), as this is the case in 90% of MS Patients [6]. The diagnosis of MS in our patient was made from the
history and the typical clinical presentation. The illness took about two
months to evolve and partial recovery from the first episode took several
months. The history of relapsing and remitting signs of corticospinal
tract dysfunction and the clinical evidence of disseminated lesions in
the CNS led us to the diagnosis of a demyelinating disease (due to a slow
virus), probably MS as the probable cause of LIS in our patient.

The
prevalence [7] of MS is less than 1 per 100,000 in the
equatorial (e.g. Nigeria).There is increasing risk of development of MS with
increasing latitude. Blacks are at lower risk than whites at all latitudes.
From the history, it was known that our patient once lived in Britain for
several years. Whether this had anything to do with the development of MS in
our patient was difficult to establish.

a.
Classic–quadriplegia and anarthria with preserved consciousness and vertical
eye movement; (b) Incomplete – the same as the classic form, but with remnants
of voluntary movements other than vertical eye movement; (c) Total–total
immobility, including absence of eye movements, and inability to communicate,
but fully consciousness. These 3 categories are further subdivided into
transient and chronic forms [26].Clinically our patient
had classic LIS (episodes I and II). Although there is no specific classification
system for vocal, cognitive, emotional, dysphagia or behavioural
recoveries; there exists one for recovery of motor function in LIS [5]: (a) No recovery– no return of motor function, total
dependence for all activities of daily living; (b) Minimal recovery– minimal
motor return, total dependence for all activities of daily living; (c)
moderate recovery – moderate motor return, independence in some, but not all
activities of daily living; (d) full recovery – independence in all activities
of daily living, but some minimal neurological deficits ; (e) No neurological
deficit – no reported residual deficits. At the end of episode I, our patient
experienced almost a full recovery; and episode II, moderate recovery.

Multiple
Sclerosis

The
fact that MS is undoubtedly a rare disease in the African continent (and as the
probable cause of LIS in our patient) makes this case very interesting.
Clinically, MS can take any of the following forms: [6,7,20] (a) Mixed (or generalized) type.
i.e. cerebrospinal type (50% of the cases);(b) Spinal form (30–40%); (c)
predominantly pontobulbar–cerebellar or cerebellar form (5%) and (d) amaurotic
form (5%). The ponto–cerebellar form has a rapid course, leading to severe
invalidism in 4 years. We believe the cause of LIS in our patient was
predominantly pontobulbar–cerebellar MS, [6,19]
which might have affected the ventral pons. There is yet another
classification of MS. 3 clinical forms of MS: (a) Relapsing-Remitting Form-
clinical progression does not occur between the attacks. There is an interval
of months or years of no clinical activity after initial episode before new
symptoms develop or original ones reoccur; (b) Secondary Progressive Form–
characterized by a gradual progressive course after initial
relapsing–remitting pattern. The disease relapses; usually with incomplete
remissions. Steady deterioration leads to increasing disability with weakness,
spasticity, ataxia, impaired vision and urinary incontinence; (c) Primary
Progressive Form – gradual progression of disability from the clinical
onset. Most likely our patient suffered from relapsing – remitting form
of MS.

Management

LIS
Management

Acute
Management [2] is similar to the care of the unconscious
patient or to that for patients with other brainstem aetiology: airway maintenance,
adequate oxygenation, adequate food and fluid intake via intravenous infusions
and nasogastric tubes, urine and bowel output drainage and clearing up;
frequent turning of patient to prevent formation of bedsores,
physiotherapy to prevent stiffness of joints and deep vein thrombosis (chest
physiotherapy must include deep breathing exercises) suctioning, postural
drainage, risk reduction, management of treatable causes, treatment of corneal
ulceration due to impaired eye closure (lateral tarsorrhaphy or botulinum
therapy), treatment of pathological crying, with selective serotonin
reuptake inhibitors.

Medical
and Nursing staff must not make casual remarks at the patient’s bedside –it may
cause the patient mental anguish [27]. Since the patient
can not communicate discomfort or wants, his/her needs must be
anticipated and met by diligent family members on hospital staff. Patient’s
needs include companionship and variety of daily experiences that a person
would crave. During rehabilitation, monitor for recovery of thumb,
finger, head and neck movements; swallowing independently, and improved
respiratory function.[2] Aggressively treat infections,
respiratory difficulties and pains. Patient – computer interfaces [24] (e.g. infrared eye movement sensors and computer voice
prosthetics) and augmentative communication devices are being developed to
assist the LIS patient communicate better [28]. Patients
with LIS are increasingly being managed in specialized centres that have
experienced manpower and equipment.

Management
of MS

·Corticosteriod
therapy: this hastens recovery from acute relapse. Long term usuage is not
advisable, as it does not prevent relapses. I.V methy1-prednisolone, 500–1000
mg daily for 3 – 7 days. [6,29]

LIS
mortality is about 60%, greatest in the first 4 months of illness, higher (70%)
in patients with vascular lesion than non-vascular causes (40%) [5].Ten
year survivor rates as high as 80% have been reported [2].
Even limited physical recovery can improve quality of life and enable the
patient to return to live with their families. Early multidisciplinary [3,5,17-24]
rehabilitation and effective nursing care reduces mortality from acute
LIS. [3] Young patients survive better. Survivors may
recover partially or completely over a period of weeks or months. The following
are some possible causes of death of LIS patients;

·Pulmonary
complications are the leading causes of death e.g. aspiration of saliva, due to
dysphagia and impaired cough reflex leads to atelectasis and pneumonia.
Immobility predisposes to pulmonary embolus [32].

·Death
from primary destructive lesions (the lesion that caused the syndrome):
cerebral infarction, haemorrhage, demyelination, trauma, encephalitis, all
involving the ventral pons and sparing the tegmentum. Our patient died from
pulmonary complication (pneumonia). Prognosis: most patients die within a few
weeks or months. A few remain locked-in for over a year before gradually
recovering [5].

Conclusion

We
have presented here a case of locked-in syndrome in a Nigerian male with
multiple sclerosis. The patient lies motionless and mute, yet conscious. The
patient with the complete syndrome signals that he or she is conscious by
opening and blinking the eyes and moving them in the vertical plane. Many
clinicians have difficulty recognizing the syndrome while evaluating the
“unconscious” patients, because they fail to routinely assess vertical eye
movement and the patient’s ability to open and blink the eyes. Diagnosis is
often made after patient’s family members or nursing staff call the attention
of the doctor to the fact that the motionless and mute patient is in fact
conscious and aware of his or her surrounding. The fact that our patient’s LIS
was probably caused by a demyelinating disease (multiple sclerosis), a
condition that is rare among blacks and in the African Continent made this case
very interesting.

We
do hope that our case report and the detailed literature review will further
enhance easy recognition and management of the syndrome by all clinicians,
especially those in Africa.

Competing
interests

We
declare that we have no conflict of interest

Authors’
contributions

Study
conception and design: KK, AA

Patient
follow-up and data collection: KK, AA

Statistical
analysis: Not applicable

Drafting
of manuscript: KK, AA

Critical
revision of the manuscript for intellectual content: AA, KK

KK
had full access to all the data in the study and takes responsibility for the integrity
of this case report and the accuracy of the literature review.

Acknowledgement

Drs.
Imananagha LN, Philip-Ephraim EE, Amene EBI and Akpan NA, for their thorough
review of the manuscript; patient’s family; staff of the Department of Medicine,
University of Calabar Teaching Hospital, Calabar, Nigeria.